Production of methyl 3-omicron-carbamyl-alpha-noviopyranoside



Unis Sttes Pate PRODUCTION OF METHYL 3-O-CARBAMYL-a- NOVIOPYRANOSIDEClifford H. Shunk, Westfield, and Karl Folkers, Plainfield, N.J.,assignors to Merck & Co., Inc., Ralrway, N ..l., a corporation of NewJersey No Drawing. Filed Dec. 26, 1957, Ser. No. 705,113

7 Claims. (Cl. 260-210) This invention relates to new sugar-likecompounds and processes of obtaining the same. More particularly, it isconcerned with methyl 3-O-carbamyl-a-noviopyranoside and processes ofobtaining the same.

The product methyl 3-O-carbamyl-a-noviopyranoside having the formula:

CHsO

-H nt ion nc'zooonm crnoJ cn C Ca CHs is useful as an intermediate inthe synthesis of novobiocin. It is an object of the present invention toprovide a novel intermediate product useful in the synthesis of methyl3-0- carbamyl-wnoviopyranoside. In addition, it is an object to provideprocesses useful for producing methyl S-O-carbamyl-a-noviopyranosidestarting with methyl-a-noviopyranoside. Other objects will be apparentfrom the detailed description hereinafter provided.

' The processes of the present invention can be shown methyl3-O-carbamyl-a-noviopyranoside In accordance with this reaction schemethe starting material methyl-a-noviopyranoside is first reacted withphosgene to produce the corresponding carbon derivative which is'thenreacted with ammonia-to produce the desired carbamyl compound. T hefirst step of; this process is effected by intimately contactingmethyl-m-noviopyranoside with phosgene in the presence of an acidacceptor. Although various basic substances can be used as the acidacceptor in this process, we prefer to use a tertiary amine such aspyridine for this purpose. The reaction is most conveniently effected ina suitable solvent medium for the reactants such as dioxane. Aftercompletion of the reaction, the product is readily recovered byconcentrating the reaction mixture and extracting it with a suitablesolvent such as chloroform.

The second step of the process is readily carried out by intimatelycontacting methyl-a-noviopyranoside 2,3- carbonate with ammonia. Thisreaction is most con veniently effected in a suitable solvent mediumsuch as methanol, ethanol and the like. After completion of the reactionthe product is recovered by concentration and crystallization of theresidue from a suitable solvent such as ethyl ether.

The following examples illustrate the processes of this invention.

EXAMPLE 1 Methyl-a-noviopyranoside 2,3-carbonateMethyl-a-noviopyranoside (1.00 g.) was dissolved in 10 ml. of drypyridine; the solution was cooled in an ice bath, and 6.2 ml. of dioxanecontaining 0.45 g. of'phosgene was added. A yellow precipitateseparated. After stirring at room temperature overnight, the mixture wasconcentrated under reduced pressure and ice water was added to theresidue. The mixture was extracted with chloroform and the extract waswashed with two portions of water, dried over magnesium sulfate,filtered and concentrated leaving 0.95 g. of methyl-a-noviopyranoside2,3-carbonate as an oil. A portion was evaporatively distilled at aboutC./0.0l mm., [a] =-33 (c.=1.5 in methanol).

Analysis.-Calcd. for C H O C, 51.70; H, 6.94. Found: C, 51.87; H, 6.78.

EXAMPLE 2 M ethyl-3-0-carbamyl-a-noviopyranoside Distilledmethyl-u-noviopyranoside 2,-3-carbonate (119 mg.) was dissolved in 12ml. of methanol containing 170 mg. of ammonia. The solution was kept atroom temperature for 22 hours after which it was concentrated underreduced pressure. Ether was added to the residual oil giving acrystalline precipiate, M.P. 178-183 C., wt. 40 mg. Recrystallization ofthe solid gave methv 3-O-carbamyl-u-noviopyranoside, M.P. 189l92.

The methyl 3-O-carbamyl-a-noviopyranoside can be converted to3-O-carbamylnoviose which is an intermediate useful in the synthesis ofnovobiocin. Thus, this compound which is also called3-carbamyl-4-methylnovobiose can be used in the synthesis of novobiocinand other novobiocin-like compounds in accordance with processesdescribed in co-pending applications Serial No. 579,130, filed April 19,1956, now abandoned, and Serial No. 705,139, filed December 26, 1957.For example, reaction of methyl 3-O-carbamylnoviose with aceticanhydride in the presence of sodium acetate at C. produces thediacetylated derivative and reaction of the latter compound withanhydrous hydrogen chloride at a temperature of 0 C. afiords1-chloro-2-O-acyl- 3-O-carbamy1noviose. Reaction of this produce with3-(3 [7,1- dimethylallyll 4 acetoxybenzamido) 4,7-dihydroxy-Z-methylcoumarin in the presence of silver oxide andhydrolysis of the condensation product with sodium hydroxide affordsnovobiocin. The 3-(3-['y,'ydimethylallyl]-4-acetoxybenzamido) 4,7dihydroxy 8- methylcoumarin is prepared by reacting Z-methyl resorcinolwith ethylcyano acetate in the presence of zinc chloride and hydrogenchloride at about C. to produce 7-hydroxy-4-imino-8-methy1-2oxochrornan, hydrolyzing this compound with 50% sulfuric acid at about100 C. to obtain 4,7-dihydroxy-S-methylcoumarin, treating this compoundin aqueous solution with sodium nitrite to produce2,4-dioxo-7-hydroxy-8-methyl-3-oximinochroman, reducing this compoundwith hydrogen in the presence of palladium on charcoal to obtain3-amino-4,7-dihydroxy-S-methylcoumarin, and condensing this compoundwith 3-(' ,'y-dimethylallyl)-4-acetoxybenzoyl chloride in water in thepresence of sodium acetate. The 3('y,'y dimethylallyl)-4-acetoxybenzoy1chloride is prepared by reacting ethyl p-hydroxybenzoate withwy-dimethylallyl bromide in toluene in the presence of sodium to obtainethyl 3-(' -dimethylallyl-4-hydroxybenzoate, hydrolyzing this compoundwith sodium hydroxide to produce the free acid, acetylating thiscompound by reaction with acetic anhydride in the presence of pyridineto obtain the 4-acetoxy compound, and reacting the sodium salt of3-('y,'y-dimethylallyl)-4acetoxybenzoate with oxallyl chloride.

The conversion of methyl 3-O-carbamyl-a-noviopyranoside toS-O-carbamylnoviose can be carried out as follows:

Methyl 3-O-carbamyl-u-noviopyranoside (1.5 g.) was heated on the steambath in 150 ml. of 0.1 N hydrochloric acid about forty-five minutes oruntil the rotation of the solution reached a constant value. Theobserved rotation of the solution at the end of this time was +0.50 in a1 dm. tube (D line of sodium used). The resulting solution waslyophilized to produce the 3-0- carbamylnoviose as a glass. [a] =+4-6(c. 1 in methanol). This product reduces Benedicts solution.

The methyl-a-noviopyranoside used as the starting material in theprocess of the present invention can be prepared in accordance withprocesses described in co-pending application Serial No. 705,110, filedDecember 26, 1957. oside can be converted to methyl ot-noviopyranosideby reactions which can be shown as follows CHOCH; FHOCHa HC-O 0 H3 H0 00 H5 H!0 CH3 H$O CHa (3H $H HO 0-H 0:?

CH; O H:

I I n Methyl 2,3-isopro Methyl2,3-isopropylidene-L-rhamnopylidene-5-keto-L iuranoside rhamnofuranosideH O OH; 1CH 0 H HO O OH; HO OH I /C\ -e H? O H HO O 0 Ha H H CH /C O H CH3 0 Ha CH; CH:

III IV Methyl 5,5-di- 5,5-dimethyl-L- methyl-2,3-isoprr lyxosepylidene-L-lyxofuranoside (3:0 --(I3-0 i EU 0 11 110-0 CH; 0 l

HO O H O C- i (3H H(]1-O 0 H3 (3311 -C H C 3 C H: (B O H C CH:

V VI

Thus, methyl 2,3-isopropylidene-L-rhamnoturan 025 p v i a a5,5-dimethyl-L- iyxono-y-lactone VII 2,3-isopropylidenenovionoone om OHSMethyl a-noviopyranosicle -OCH:

HO-OH HOOH CHKOSEH CH3 CH3 Noviopyranoside Methyl-B-noviopyranoside CH3I In the foregoing depicted reactions the starting matenial is firstreacted with an oxidizing agent to produce methyl2,3-isopropylidene-5-keto L rhamno furanoside, which upon reaction witha methyl magnesium halide, is converted to methyl5,5-dimethyl-2,3-isopropylidene-L- lyxofuranoside. This latter compoundis then hydrolyzed by reaction with a non-oxidizing inorganic acid toobtain 5,5-dimethyl-L-lyxose which is then oxidized to produce5,5-dimethyl-L-lyxono-y-lactone. Conversion of5,5-dimethyl-L-lyxono-y-lactone to the corresponding 2,3-isopropylidenederivative and methylation of the sodium salt of this intermediateresults in the production of 2,3-isopropylidenenoviono-6-lactone. Uponhydrolyzing 2,3-isopropylidenenoviono-a-lactone with a non-oxidizinginorganic acid noviono-fi-lactone is obtained When novionofi'lactone isreduced by reaction with suitable reducing agents noviopyranoside isobtained, which upon methylation is converted to a mixture ofmethyl-m-noviopyranoside and methyl-B-noviopyranoside. The mixture ofmethyl-a-noviopyranoside and methyl- S-noviopyranoside can then beseparated by fractional crystallization from suitable solvent mediums toproduce methyl-otnoviopyranoside and methyl-,B-noviopyranoside.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of our invention.

What is claimed is:

1. The process which comprises reacting methyl m-noviopyranoside withphosgene in the presence of an acid acceptor to produce methyla-noviopyranoside 2,3- carbonate.

2. The process according to claim 1 wherein the acid acceptor is atertiary amine.

carbonate and reacting methyl a-noviopyranoside 2,3- carbonate withammonia to produce methyl 3-O- carbamyl-a-noviopyranoside.

7. The process which comprises intimately contactingmethyl-a-noviopyranoside with phosgene in the presence of pyridine toproduce methyl-oc-noviopyranoside 2,3- carbonate, and reactingmethyl-a-noviopyranoside 2,3- carbonate with ammonia in methanol toproduce methyl 3-O-carbamyl-a-noviopyranoside.

No references cited.

1. THE PROCESS WHICH COMPRISES REACTING METHYL A-NOVIOPYRANOSIDE WITHPHOSGENE IN THE PRESENCE OF AN ACID ACCEPTOR TO PRODUCE METHYLA-NOVIOPYRANOSIDE 2,3CARBONATE.